c-Met, a hepatocyte growth factor (HGF) receptor, is one of receptor tyrosine kinases. It dimerizes when HGF binds thereto and then, autophosphorylation of the tyrosine residue occurs. As a result, signaling of the MAPK pathway or Akt pathway is activated and cell growth is promoted, while induction of cell apoptosis is inhibited. These phenomena may cause canceration of cells so that c-Met is expected as a potent molecular target in cancer therapy. In fact, various anticancer agents targeting HGF or c-Met are under development.
In recent years, a variety of peptide drugs have been researched and developed. Due to chemical and biological diversity, peptide drugs tend to have higher specificity than low molecular compounds in interaction with target molecules. As a result, they can obtain greater physiological activity.
On the other hand, peptide drugs are likely to be degraded in a short time because of inferiority in protease resistance to large proteins such as antibiotics. Improvement in such a problem of peptide drugs has been investigated recently by adding various modifications to them.
The present inventors has developed artificial aminoacylated RNA catalyst “flexizyme” (for example, Non-patent Document 1) so far. Flexizyme is an artificial RNA catalyst having aminoacyl tRNA synthetase-like activity and it is capable of linking an arbitrary amino acid to an arbitrary tRNA. Using flexizyme enables binding of a desired amino acid to a tRNA having a desired anticodon so that a genetic code table can be reprogrammed by making an amino acid correspond to an arbitrary codon different from that of a natural genetic code. This is called “codon reassignment”.
Codon reassignment using flexizyme makes it possible to introduce an arbitrary amino acid including a non-proteinogenic amino acid into an arbitrary position of a peptide. The resulting peptide may have enhanced protease resistance, cellular permeability, or affinity or specificity for a target molecule.
In recent years, on the other hand, macrocyclization of peptides has attracted attentions. Macrocyclic peptides can be found in the natural world and they are known to have stable conformation. Due to their size and complexity, macrocyclic peptides are known to show specificity higher than that of small non-cyclized peptides (for example, Non-Patent Document 2) and are expected to serve as an inhibitor against highly difficult targets such as molecules whose protein-protein interaction is unknown, or molecules whose binding site for a low molecular compound is unknown. Constraint by the cyclic structure is thought to improve the bioavailability of peptides or their resistance against metabolism.
In the study of providing various modifications to peptides as described above, there is a demand for the development of peptides excellent in resistance against metabolism or stability in vivo.